Wound care device

ABSTRACT

Wound care device comprising chitosan, said chitosan being capable of absorbing liquid to form a swollen, coherent gel, and said chitosan being in the form of fibres having been modified by treatment with acid in a solvent which is not able to dissolve the chitosan fibres and by treatment with heat.

This patent application is a continuation of patent application Ser. No.10/089,073 filed Apr. 8, 2002, now U.S. Pat. No. 6,998,509 and isincorporated by reference herein as if set forth in the specification inits entirety.

FIELD OF THE INVENTION

The present invention relates to a wound care device comprisingchitosan, said chitosan being capable of absorbing liquid to form aswollen, coherent gel, and a method of preparation of the same.

BACKGROUND OF THE INVENTION

In the treatment of exuding wounds there is a need for an absorbentdressing being capable of adapting to the conformation of the individualwound. This may be done by using fibre dressings or hydrogels.

Wound care devices comprising fibres may be based on polysaccharidefibres, which are usually water insoluble, but water absorbing. They arein general based on alginate or CMC. Wound care products such asdressings or fillers based on alginate or CMC, may be able to absorb upto 15–25 g exudate/gram product, with limited swellablity andgellability. These fibre dressings/fillers are normally supplied assterile.

The use of fibres often suffers from the drawback of a limitedabsorption and/or lack of cohesion, leading to difficulties with respectto removing the fibre product from the wound as the product does notconstitute a cohesive part.

Methods of preparing alginate fibres are well known. Normally sodiumalginate is completely converted into insoluble calcium alginate fibres.Methods for enhancing the solubility of alginate fibres are also wellknown. International Patent Application No. WO 94/17227 discloses amethod for preparing highly absorbent alginate fibres by conversion ofcalcium alginate fibres into alginic acid fibres.

In International Patent Application No. WO 94/16746 is disclosed aprocess of preparing carboxy methyl cellulose fibres which are gellable,but still coherent enough to be removed from a wound in one piece.

European Patent Application No. 627 225 discloses a method for preparinga superabsorbent chitosan powder, being capable of absorbing liquid manytimes it own weight by forming a transparent gel. This is done bytreating the powderous chitosan with an acid, preferably a hydroxycarbon acid like lactic acid or hydroxy butylic acid. The resultingpowder is capable of absorbing high amounts of water by forming a gel.

The acid-modified chitosan disclosed in EP 627 225 A2 is suitable foruse as a superabsorbent in diapers and like products, in which thepowdered material will be encapsulated and little or no coherence isdemanded. However, the reference is silent with respect to preparationof highly coherent material, for use in e.g. wound care products.

Published Japanese Patent Application No. JP 9-69654-A discloses amethod for preparing partly deacetylated chitin fibres for wound care.The preferred chitin material has a deacetylation degree of max. 90%,preferably 40–60%. The material is not used as an absorbent, but as ahaemostatic agent for stopping bleeding wounds.

In European Patent Application No. 171 254 is disclosed chitin fibresbeing treated in an aqueous solution with acid and elevated temperature.The fibres remain their structure due to the fact that chitin is notsoluble in an acidic aqueous solution.

Contrary to chitin, chitosan is soluble in an acidic aqueous solution.

International Patent Application No. 97/29132 discloses chitosan beingdissolved in a weak acidic aqueous solution. The chitosan is treatedwith a carboxylic acid polyanhydride as a cross-linking agent. Theresulting hydrogel may subsequently be processed into powders or fibres.

Thus, there still is a need for a wound care device comprising amaterial being capable of absorbing large amount of liquid by gelling,having a three-dimensional structure in the form of fibres, and having ahigh degree of cohesion after absorption. The need is fulfilled by thewound care device of the present invention.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1. Shows the wound dressing device comprising chitosan.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to a wound care device comprisingchitosan, said chitosan being capable of absorbing liquid to form aswollen, coherent gel.

The present invention further relates to a method of preparation of awound care device comprising chitosan being capable of absorbing liquidto form a swollen, coherent gel.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a wound care device comprising chitosan, saidchitosan being capable of absorbing liquid to form a swollen, coherentgel, and said chitosan being in the form of fibres having been modifiedby treatment with acid in a solvent which is not able to dissolve thechitosan fibres and by treatment with heat.

The fibrous structure of the chitosan according to the present inventionmay provide a essential coherence for use in a wound dressing. When usedas e.g. a wound contacting fabric, it is important that the absorbentmaterial is coherent rendering it possible to remove the wound dressingin one piece from the wound.

A fibre is in this application defined as an elongated member whereinthe proportion between length and diameter of the member is at least 25.This definition includes filaments as well.

Chitosan fibres may be used as raw material. In principle, all types ofchitosan fibres may be used. The preparation of the modified chitosanfibres according to the invention may be optimised depending on thequality of the raw material. Parameters such as fibre diameter,molecular weight of chitosan, degree of deacetylation and source ororigin of the chitosan may influence on the process.

Chitosan fibres are usually made from chitosan of a relatively lowmolecular weight.

It is preferred that the molecular weight of the chitosan used for thepreparation of the wound care device according to the present inventionis less than 750.000, more preferred less than 400.000, and even morepreferred less than 250.000, and most preferred less than 175.000.

Most preferred is chitosan with a molecular weight lower than 300.000.

Chitosan fibres suitable for use in this invention are fibres with adeacetylation degree above 65%, more preferred above 75% and mostpreferred above 85%.

The viscosity of the chitosan used according to the invention maypreferably be less 1000 cP, more preferred less than 500, even morepreferred less than 300. The most preferred viscosity is from 40 to 200cps. The viscosity is measured on a 1% w/w chitosan dissolved in anaqueous solution of 1% w/w acetic acid on a Brookfield LVT viscometer,25° C., appropriate spindle at 30 rpm.

Preferably, the fibres are having a minimum average length of 3 mm. Thepreferred proportion between length and diameter of the fibres is atleast 25, more preferred at least 80 and most preferred at least 200.

The invention also relates to a method of preparation of a wound caredevice comprising chitosan being capable of absorbing liquid to form aswollen, coherent gel, said method comprises the steps of

-   a) suspending the chitosan in the form of fibres in a non-solvent    comprising acid-   b) isolating the resulting modified chitosan fibres from the    non-solvent-   c) treating the chitosan fibres with heat during step a) or/and b).

The chitosan is according to the present invention modified by treatmentwith acid and heat. This treatment is converting the chitosan fibresfrom a water insoluble, non swelling and non gelling state into chitosanfibres which are water swelling, water gelling but still substantiallywater insoluble and with a coherent structure.

By the terms water swelling, water gelling but substantiallywater-insoluble is meant that when the fibres are contacted with anaqueous liquid, such as wound exudate, they will absorb liquid and swellby forming a gel. The fibre structure will still be detectable. Thefibres will turn from non-transparent into relative transparent fibres.The fibres are not completely water-insoluble (few molecules maydissolve), but the material is sufficient water-insoluble and coherentto render it possible to remove the fibres from a wound in one piece.

The non-solvents used according to the present invention may be anynon-solvent to chitosan. Preferably, the non-solvent has a boiling pointhigher than 50° C. and even more preferred a boiling point between 60and 250° C.

Suitable acids for this embodiment of the invention may be any lowmolecular organic acid.

The preferred acids are organic acids such as formic, acetic, halogenacetic acids (such as fluoro or chloro acetic acid), propanoic,propenoic, lactic, acrylic glyoxylic, pyruvic or a hydroxypropionic/butanic acid.

The more preferred organic acids used for modification of the chitosanfibres in the wound care device according to the invention may be ahydroxy or acyl organic acid, which is soluble in the used non-solvent,preferably glucolic, glyoxylic, pyruvic, lactic or a hydroxypropionic/butanic acid.

The most preferred acid is lactic acid.

Preferably, the quantity of acid used in the modification processaccording to the present invention is from 2 mmol to 20 mmol per gramchitosan, more preferred from 3 to 15 mmol acid per gram chitosan andmost preferred from 4 to 10 mmol acid per gram chitosan. Higher amountsof acid will not change the result in neither a positive nor negativeway, and is therefore considered to be unnecessary.

The heat treatment of the chitosan fibres may be conducted at anytemperature above 50° C.

The preferred temperature of the heat treatment of the chitosan fibresis between 50–250° C., more preferred from 60 to 225° C.

The modified fibres according to this invention have preferably anabsorption higher than 20 g/g, more preferred higher than 25 g/g andmost preferred higher than 30 g/g.

The wound care device according to the invention may be in the form of afibre rope, woven, knitted or non-woven sheets or pouches or it may bein the form of an island dressing, with an absorbent centre part basedon the modified chitosan fibres and an adhesive film covering andextending further than the absorbent part.

The wound care device according to the invention may be based on a wovenor non-woven fabric comprising the modified chitosan fibres, which iswater swellable and gellable.

The wound care device may have a minimum absorption of 0.20 g/cm2.

The absorption of the wound care device according to the invention ispreferably minimum 0.20 g/cm2, more preferred minimum 0.25 g/cm2 andmost preferred more than 0.30 g/cm2.

If the modified chitosan fibres are preferably in the form of a woundcavity filler such as a fibre rope, the total absorption of the rope ismore than 20 g/g, preferred more than 25 g/g and most preferred morethan 30 g/g.

The wound care device according to the present invention is especiallysuitable for treatment of leg ulcers, burns, pressure sores, diabeticulcers, cancer wounds and acute wounds.

In a first embodiment of the invention the acid treatment and the heattreatment is a combined process, according to which the chitosan fibresmay be treated with acid under simultaneous heat treatment.

In the first embodiment of the invention the temperature of which theacid treatment is processed is preferably from 50 to 200 more preferredfrom 60 to 180° C. and most preferred from 64 to 160° C.

In a second embodiment of the invention, the acid is a mixture of atleast two acids.

The first acid may be a hydroxy organic acid, which is soluble in theused solvent, preferably glucolic or a hydroxy propionic/butanic acid.Especially preferred is lactic acid.

When chitosan molecules are treated with acids of the first type at atemperature below 85° C., very weak and few crosslinking point betweenthe chitosan molecules are created. This will turn the chitosan from aninsoluble form into almost soluble form with very limited cohesion. Ifthe material is sterilised by radiation this will result in an evenlower cohesion. Thus, there is a need for additional cohesion. This maybe obtained by adding the second type of acid to the treatment.

The first acid is imparting gelling and swelling ability to the chitosanfibres and the second acid is imparting cohesion to the fibres.

The second acid will provide the fibres with substantially insolubilityand cohesion. The cohesion may be obtained as a result of intermolecularcrosslinking between the chitosan molecules, where the chitosanmolecules may form an acid salt with the second acid.

The second acid may be an inorganic sulphur or phosphor acid or anyorganic acid except hydroxy acids, which is soluble in the usednon-solvent. Preferred organic acids may be: Formic, acetic, propanoic,butanoic and propenoic acid. Also halogenated derivative of these suchas chloro acetic acid may be used.

It is preferred that the second acid is an inorganic sulphur or phosphoracid or one of following organic acid: Formic, acetic, propanoic,butanoic and propenoic acid, or a halogenated derivative of these suchas chloro acetic acid.

It is especially preferred that the second acid is formic, acetic,propanoic or propenoic acid.

The first acid may comprise 20–100% of the total acid content, morepreferred 40–97% and most preferred 60–95% of the total acid content.

The second acid may comprise 0–80% of the total acid content of thesolution, more preferred 3–60%, and most preferred 5–50% of the totalacid content.

It is preferred to let the acid treatment last until the desired levelof crosslinking occurs. By reducing the reaction time of the process,the chitosan fibres may have been converted to a chitosan acid salt, butthe molecules have not yet crosslinked. This results in more or lesswater soluble chitosan fibres, which is not desired.

The process time for the combined acid and heat treatment may suitablybe more than 0.5 hours, preferably more than 4 hours, dependent on thetemperature of the heat treatment.

If the treatment is prolonged to more than 4 hours, it may be possibleto use only acid of the first type, especially if the temperature isbelow to 85° C., and still obtain a highly cohesive wound care device.

By combining the above specified first and second acid in the specifiedamount, the resulting fibres are water swellable and gellable, but stillwater insoluble rendering it possible that a wound care dressingcomprising these modified chitosan fibres may be removed in one pieceafter having absorbed wound exudate.

Combinations of acids within each group of either first or second acidgroup may also be applied.

Especially preferred is a mixture of lactic acid and any low molecularweight organic acid (molecular weight<300 g/mole).

Most preferred is an acid mixture of lactic acid and formic, acetic,propanoic or propenoic acid.

The combined acid and heat treatment of the chitosan in this embodimentof the invention may be conducted at a temperature of 50–85° C., morepreferred from 60 to 85° C., even more preferred from 64 to 85° C. andmost preferred at the boiling point of the non-solvent.

In a third embodiment of the invention, the acid treatment is conductedat a high temperature, above 85° C. When the temperature is kept above85° C. in the acid treatment, only one acid is necessary to achieve thepreferred properties of the chitosan fibres.

The preferred acid used in the modification of the chitosan fibres ofthis embodiment of the invention is an hydroxy organic acid, which issoluble in the used solvent, preferably glucolic or a hydroxypropionic/butanic acid.

Especially preferred is lactic acid.

Mixtures of acids may also be used.

The temperature at which the treatment is conducted is preferably from85 to 200° C., more preferred from 85 to 180° C. and more preferred from85 to 160° C. and most preferred form 90 to 160° C.

The used non-solvent can be any non-solvent, preferably with a boilingpoint above 85° C. Most preferred is alcoholic solvents such aspropanol, isopropanol and butanol.

The duration of the acid treatment depends of the type and quantity ofacid, the quantity of water and the temperature. The process time mayvary from seconds to several hours. The higher temperature and quantityof acid and water, the shorter time is needed to achieve the desiredproperties of the chitosan fibres.

The higher concentration of acid during the acid treatment, the shortertime is needed to convert the chitosan fibres.

In a fourth embodiment of the invention, the acid treatment is notconducted at an elevated temperature. After the acid treatment, thefibres are isolated from the acid solution and subsequently subjected toa heat treatment, e.g. in an oven, at an elevated temperature.

In general, the acid treatment will turn the chitosan fibres frominsoluble and low absorbent into water soluble, or if the acid treatmentis limited, partly soluble and partly water insoluble. The solubility isa consequence of that the chitosan molecules are in the acid treatmentconverted to chitosan acid salts molecules. Therefore the acid treatmentinfluences the subsequent heat treatment and the performance of themodified fibres.

Acids suitable for this embodiment of the invention are low molecularweight inorganic acids and organic acids such as formic, acetic, halogenacetic acids (such as flouro or chloro acetic acid), propanoic,propenoic, lactic, acrylic, glyoxylic, pyruvic or a hydroxypropionic/butanic acid, more preferred organic acid such as formic,acetic, propanoic, propenoic, lactic, acrylic, glyoxylic, pyruvic or ahydroxy propionic/butanic acid.

Most preferred is lactic acid.

In this embodiment of the invention one acid or a mixture of two or moreacids may be used. Mixtures may be any suitable mixture such as lacticacid and any low molecular weight organic acid (molecular weight below300 g/mole and soluble in the non-solvent).

The temperature during the acid treatment should be kept so low, thatthe fibres do not form a gel after the treatment, but dissolve when theyare contacted with water.

The temperature during the acid treatment is preferably from thefreezing point of the solvent and up to 80° C., depending on whattemperature the fibres start to gel. The temperature is more preferredkept from −10 to 64° C., and even more preferred kept at −10 to 40° C.,and most preferred kept at room temperature.

The duration of the acid treatment should be until a sufficient numbersof amine groups have been protonated so the chitosan fibres will form agel after the heat treatment if contacted with an aqueous liquid. Theduration of the acid treatment depend on the amount of water, type ofacid, amount of acid and the type, shape or origin of the chitosan.

The size of the chitosan fibres is also important. The larger diameterof the fibres, the longer acid treatment time is needed.

The duration of the acid treatment may, depending on the water amount,acid concentration, temperature and chitosan fibres be treated from afew seconds to many hours before the treatment is ended.

If the acid treatment is carried out with 6% water, ethanol and 7.5 mmolacetic acid per gram chitosan fibres (100 gram non-solvent per 10 gramchitosan fibres), the acid treatment of the chitosan fibres will afteronly 10 minutes acid treatment at room temperature be almost completelysoluble in water.

After the acid treatment the fibres may be washed in an alcohol toremove residual acid, and subsequently dried.

Hereafter the fibres may be subjected to a dry heat treatment. The heattreatment may be carried out at an elevated temperature, preferably from60 to 250° C., more preferred 80 to 250° C. and most preferred at 100 to200° C.

During the heat treatment, the chitosan fibres will turn from watersoluble to water swellable, gellable and substantially water insoluble.

The duration of the heat treatment depends on the temperature of theheat treatment and the choice of acid. If the dry heat treatment iscarried out at 100° C., the heat treatment has a duration of preferably0.5 to 8 hours, depending on which acid is used. The higher temperaturein the heat treatment, the shorter time is needed to convert the fibresfrom water soluble to swellable, water absorbent and gellable. If theheat treatment is carried out at 175° C. only a few minutes or evenseconds are needed to convert the fibres to gellable and more insoluble.

The more severe heat treatment, the less swellable the fibres becomes.The more gentle heat treatment, the more swellable becomes the fibres,and optionally water soluble. Therefore the heat treatment should beoptimised so the chitosan fibres after the heat treatment are waterswellable and substantially water insoluble.

In this embodiment of the invention, it is preferred to conduct the acidtreatment at room temperature with 4 to 10 mmole acid, e.g. 80% lacticacid and 20%, acetic acid, per gram chitosan, rinse the fibres inethanol and heat treat the fibres at 160° C. in 10 minutes. The fibresare processed into a non-woven fabric, packed and sterilised.

In a fifth embodiment of the invention the chitosan fibres are firsttreated with acid, and subsequently treated with a base. In this way,the fibres are first converted to water soluble fibres by the acidtreatment, and are then turned into water swellable but substantiallywater insoluble absorbent fibres by the alkaline treatment.

In a sixth embodiment of the invention, the chitosan fibres are treatedwith heat both during the acid treatment and then again subsequently.

In a seventh embodiment of the invention the amount of acid used isinsufficient for a complete conversion of the chitosan, resulting infibres which are water swellable, water gelling but substantially waterinsoluble. The resulting chitosan fibres will thus comprise non-modifiedparts where the absorption is lower but the cohesion is higher than inthe parts where the chitosan is fully converted. This combination mayreduce the risk of gel-blocking in the fibrous material, as well as thehigher cohesion may ease the further processing and handling of thefibres.

By treated in such a limited way is meant, that the chitosan fibres mayonly be partly converted into a acid salt, in such a manner that themolecules will expand when they contacted with an aqueous liquid, butstill maintain their structure in such a degree, that removal in onepiece from a wound is possible. The process of carrying out thisembodiment of the invention is preferably by reducing amount of acid inthe acid treatment. By doing this, the acid will not be able to completethe conversation of chitosan into a chitosan salt.

In this embodiment the fibres may be treated as in the first and thesecond embodiment of the invention, but only with a minimal amount ofacid. The amount of acid is from 2 to 7.5 mmole acid per gram chitosanpreferably 3–7.5 mmole acid per gram chitosan and most preferred from 5to 7 mmole acid per gram chitosan.

The fibres are optionally treated with acids of the first type. The mostpreferred acid is lactic acid.

In an eighth embodiment of the invention, the used chitosan fibres are“never-dried” chitosan fibres. By using “never-dried” chitosan fibres,the process for modifying the fibres may be adjusted in such a manner,that water absorbent, gellable and substantially water insoluble fibresstill may be obtained after the modification process. This is preferablydone by treating the fibres more gentle than if dried fibres were usedin the modification process.

Another way of improving the strength of the chitosan fibres, is coatingor impregnating an anionic material onto the modified fibres. Anionicpolysaccharides such as carboxy methyl cellulose (CMC), alginate,carrageenan or pectate may be preferred as coating or impregnationmaterial.

In a ninth embodiment of the invention strength is added to the modifiedchitosan fibres by adding anionic fibres.

In a wound care device more strength and cohesion may be desired. Thismay be obtained by adding fibres other than chitosan to the device.These fibres may be blended with the chitosan fibres or be woven, or bein separate layers.

These anionic fibres may be fibres such as alginate or carboxy methylcellulose fibres. When the anionic fibres are added to the modifiedchitosan fibres, they will, when the fibres are contacted with woundexudate, open up their structure and a crosslinking between the anionicmolecule group and the modified chitosan molecule group will occur.

The amount of anionic fibres in a wound care device according to thepresent invention is preferably between 5 and 60% and more preferredbetween 10 and 50%.

The process of adding anionic fibres could be any suitable process, oneexample of such a process could be by carding both the modified chitosanand the anionic fibres into a carded fibre mixture.

An other way of manufacturing could be to make yarn of both the modifiedchitosan and the anionic fibres and weave the fibres into a wovenfabric.

In a tenth embodiment of the invention, the modified chitosan fibres aremixed with unmodified chitosan, cotton, wool or viscose fibres or thelike, and processed into a woven or non-woven fabric, obtaining aproduct which is water insoluble and low absorbent cotton, wool orviscose and water gellable, water swellable, highly water absorbent andsubstantially water insoluble modified chitosan fibres.

The above mentioned fabric may be manufactured by mixing the chitosanand the other fibres before or after the modification of the chitosan.The fibres may be spun into a yarn of e.g. cotton and chitosan,comprising preferably 5–95% modified chitosan and more preferably 10–90%modified chitosan, and most preferred 25–75%, depending on the use ofthe fabric.

If the fabric is to be used for low exuding wounds, a dressing with alow amount of modified chitosan fibres is desired, but if the fabric isto be used on highly exuding wounds, a higher amount of modifiedchitosan fibres is requested. The process of preparing this embodimentof the invention may be the same process as described in the 9thembodiment of the invention.

An other process of preparing the wound care device may be to processchitosan fibres into yarn and then modify the chitosan yarn to obtainyarn of modified chitosan. The yarn is weaved with any of the abovedescribed nonionic fibres.

In both the ninth and the tenth embodiment of the invention lesscohesive modified chitosan fibres may be used, as the added non modifiedchitosan fibres will provide strength and cohesion to the resultingwound care device.

In an eleventh embodiment of the invention the chitosan material may bepresent in the form of powder, then first modifying chitosan powder withacid and heat, and then process the modified powder particles intofibres. The modified fibres are subsequently processed into a woundcare-device.

In a twelfth embodiment of the invention the modified chitosan fibresare processed into a non-woven fabric The non-woven fabric may be formedby randomly laying, for example dry-laying, and/or cross-laying thefibres followed by needling. Alternatively a non-woven fabric may beformed by cross-laying the modified chitosan fibres while partiallymoist, followed by drying, optionally under pressure.

The non-woven product may be used as a wound dressing or as a woundcontacting layer of a wound care product.

In a thirteenth embodiment of the invention the wound care devicecomprises one or more active ingredients, e.g. a pharmaceuticalmedicament. This opens for a combined medical treatment of a wound,where the fibres absorb wound exudate and the pharmaceutical medicamentswill be applied to the wound. The pharmaceutical medicaments will eitherbe incorporated in the wound care device or migrate to the wound surfaceand promote its function.

Examples of such pharmaceutical medicaments includes a cytochine such asa growth hormone or a polypeptide growth factor such as TGF, FGF, PDGF,EGF, IGF-1, IGF-2, colony stimulating factor, transforming growthfactor, nerve stimulating growth factor and the like giving rise to theincorporation of such active substances in a form being apt to localapplication in a wound in which the medicament may exercise its effecton the wound, other medicaments such as bacteriostatic or bactericidalcompounds, e.g. iodine, iodopovidone complexes, chloramine,chlorohexidine, silver salts such as sulphadiazine, silver nitrate,silver acetate, silver lactate, silver sulphate, silver sodiumthiosulphate or silver chloride, zinc or salts thereof, metronidazol,sulpha drugs, and penicillin's, tissue-healing enhancing agents, e.g.RGD tripeptides and the like, proteins, amino acids such as taurine,vitamins such ascorbic acid, enzymes for cleansing of wounds, e.g.pepsin, trypsin and the like, proteinase inhibitors or metalloproteinaseinhibitors such as Illostat or ethylene diamine tetraacetic acid,cytotoxic agents and proliferation inhibitors for use in for examplesurgical insertion of the product in cancer tissue and/or othertherapeutic agents which optionally may be used for topical application,pain relieving agents such as lidocaine or chinchocaine, emollients,retinoids or agents having a cooling effect which is also considered anaspect of the invention.

In a fourteenth embodiment of the invention, the chitosan fibres arepartly carboxy methylated, and due to this turned from insoluble and lowabsorbent and into highly absorbent, gelling and substantially waterinsoluble. This is achieved by treating the chitosan fibres with awater/alcohol solution containing sodium hydroxide and the sodium saltof chloro acetic acid. The treatment is carried out at an elevatedtemperature.

The temperature and time of the treatment will depend of theconcentration of the sodium hydroxide, water and the sodium salt ofchloro acetic acid. However a preferred temperature for the treatmentmay be 40 to 180° C., more preferred 50 to 140 and most preferred 50 to120° C.

The duration of the treatment depends on the process parameters, howeverthe preferred reaction time is from 1 minute to 24 hours.

If the fibres are completely carboxy methylated, the fibres will becomewater soluble and thus not useful as such in a wound care dressingdemanding coherence. Therefore it is important that the chitosan fibresonly are partly carboxy methylated, so the chitosan fibres become waterabsorbent, water swellable and substantially water insoluble.

The preferred degree of carboxy methylation should be between 0.1 and0.9, more preferred from 0.25 to 0.75 and most preferred from 0.3 to 0.6(the number refers to how many carboxy methyl units there are permonosaccharide).

The process of partly carboxy methylating chitosan fibres could be anysuitable process, such as treating the chitosan fibres with a mixture ofan alcohol, water, sodium hydroxide and the sodium salt of chloro aceticacid.

The invention is explained more in detail in the working examples belowdisclosing embodiments and properties of the wound care device of theinvention. It is evident that many variations may be made withoutdiverging from the invention the scope of which is set forth in theappended claims.

EXAMPLES

Method of Measuring Absorption of Free Fibres in Water

A weighted (W1) amount (app. 0.2 grams) of the fibre sample was cut andput into a bag made of polyethylene net. Then the sample was placed in avessel containing excess amounts of solution A (142.5 mM NaCl and 2.5 mMCaCl₂). After one hour the sample was removed from the solution and heldover the solution for ½ minute, whereafter the weight was measured (W3)and the sample was returned into the vessel. After 24 hours, again theweight of the sample was measured as before (W4). The weight of a wet,empty PE-net bag was also measured (W2). W2 is a average value of 10measurements.

The absorption of the fibre sample was calculated as:

Absorption after 1 hour (g/g):(W3−W2−W1)/W1Absorption (after 24 hours) in g/g:(W4−W2−W1)/W1The Absorbency of a Non-Woven Fabric:

A piece of 4×4 cm was cut and weighted (W1). The sample was put into apetri dish containing excess solution A for 4 hours. Hereafter thesample was removed and allowed to drip off for ½ minute, whereafter theweight was measured (W2).

The absorption (in g/cm²) was calculated as:(W2−W1)/16Cohesion of the Modified Chitosan Fibres:

This test method is a qualitative measurement of the gellability,solubility and cohesion of wet fibre samples.

A fibre sample was soaked saline water (solution A) for 24 hours. Afterthe 24 hours, the sample was qualitatively evaluated and categorisedinto one of following categories:

-   0 The sample is completely water soluble. The absorption is not    measurable as the sample dissolves out of the PE-net-   1 The sample is almost water soluble with only limited gellability.    The cohesion of the gel is extremely low. The absorption may be    measurable, but still some parts of the sample may have dissolved    out of the PE-net.-   2 The sample is partly water swellable and partly gellable. Some    chitosan molecules seems to dissolve (the gel is greasy). The fibre    structure is slightly visible after absorption. The gelled mass has    some cohesion, so removal in one piece may be possible.-   3 The sample is gelled. The fibres are cohesive, water swellable and    transparent. The gelled fibres still maintain their fibre structure    and removal in one piece is easy to obtain. The fibres are no longer    greasy.-   4 The sample is partly gellable and partly water insoluble. The    sample is more transparent than untreated fibres and have a very    high cohesion. If pressure is put on the fibres, clear fibres, “dry    fibres”, can be seen. It may be possible to separate single fibres    from the sample.-   5 The sample is water insoluble with only minimal swellability.

In the wound care device according to the present invention thepreferred cohesion of the modified chitosan fibres are in the area of 2or 3 in the above categories. If a modified fibre sample evaluate to 2or 3, removal in one piece seems to be possible.

Materials Used in the Examples:

-   Chitosan fibres from R C Biochemical Co. Ltd., Pusan, South Korea-   (The fibres have a degree of deacetylation of above 90%)-   Chitosan powder (TM 370, particles<100 micro) from Primex    ingredients,-   Norway-   100% acetic acid (glacial) from Merck.-   90% lactic acid from Merck.-   Sodium hydroxide from Merck.-   Calcium alginate fibres (SeaSorb filler) from Coloplast A/S, Denmark-   Carboxy methyl cellulose fibres (Aquacel) from ConvaTec, Ltd, UK.-   Destilled water.-   96% Ethanol from Danisco, Denmark.-   1-Propanol from Merck.-   1-Butanol from Merck.-   Solution A (142.5 mM NaCl and 2.5 mM CaCl₂ in distilled water).

Example 1a

Chitosan Fibres Treated with Combined Acid and Heat.

In a reaction vessel 200 grams of 96% ethanol was mixed with 12 grams ofwater and 150 mmole acid. To this solution 20 grams of chitosan wereadded and the suspension was treated at the boiling point of thesuspension for app. 4 hours under reflux. The fibres were then washedtwice in ethanol. Each sample was sterilised by 1*30 kGy electron beam.Hereafter the absorption and cohesion of the fibres were measured.

Table 1 is showing the absorption and cohesion of the samples, measuredon sterilised samples. The absorbency was measured as doublemeasurements.

TABLE 1 Mole % Absorption Absorption Cohesion Sample acetic acid* (g/g)1 hour (g/g) 24 hours (category) 1a 0 29 56 1–2 1b 10 37 55 2 1c 20 2250 2–3 1d 30 21 31 3 1 50 12 12 4 1f 80 8 8 5 1g 100 4 4 5 *Of totalacid content. The remaining acid content was lactic acid.

The dry modified chitosan fibres were relative soft and suitable forincorporation in wound care devices such as wound dressings.

Example 1a is showing, that the higher concentration of acetic acid usedin the treatment of the fibres, the less absorbent and the moreinsoluble the fibres becomes. The optimal wound dressing has a maximumabsorption, but just enough acid of the second type which gives thefibres insolubility, so the wound dressing can be removed in one piecefrom a wound.

Example 1b

Preparation of a Wound Dressing.

A tow of sample 1c (non-sterile) was cut to 50 mm lengths and a wounddressing was formed by first carding the cut fibres to form anapproximate 20 g/m² web, then cross folding the this web needling toprovide a resultant non-woven fabric of approximately 100 g/m², then a10 cm×10 cm square was cut to form the fabric. The fabric square waspackaged and sterilised using an electron beam dose of 30 kGy.

The non-woven wound care product had an absorbency of 51 g/g and 0.52g/cm².

Alternatively the tow itself may be cut for example to 40 cm lengths,packed and sterilised. Hereafter it may be used as a wound cavityfiller.

Example 2a

Chitosan Fibres Treated with Acid and Heat.

In a reaction vessel 200 grams of 96% ethanol was mixed with 150 mmolelactic acid. To this solution 20 grams of chitosan were added and thesuspension was treated at the boiling point of the liquid for app. 4hours under reflux. The fibres were then washed twice in ethanol. Thesample was sterilised by 1*30 kGy electron beam. Hereafter theabsorption and cohesion of the fibres were measured.

Table 2 is showing the absorption and cohesion of the sample (measuredas triple measurements).

TABLE 2 Sample Absorption (g/g) Absorption (g/g) Cohesion No. 1 hour 24hours (category) 2 27 47 2

The modified fibres were soft and flexible and very suitable for wounddressings.

Example 2 demonstrates, that the amount of water has an limitedinfluence on both the absorption and cohesion of the fibres, when theyare treated at the boiling point of the ethanol. When the fibres aretreated without additional water in the reaction vessel, the absorptiondecreases and the cohesion increases slightly.

Example 2b

Preparation of a Non-Wowen Fabric.

A non-sterile sample of sample 2a was cut to 50 mm lengths and a woundcar device was formed by first carding the cut fibres to form anapproximate 20 g/m² web, then cross folding the web needling to give aresultant non-woven fabric of approximately 100 g/m², then a 10 cm×10 cmsquare was cut to form a fabric. The fabric was packed and sterilisedusing an electron beam dose of 30 kGy.

The non-woven wound care product had an absorbency of 49 g/g and 0.49g/cm².

Alternatively, the tow itself is cut for example in 40 cm lengths, maybe packed and sterilised. Hereafter it may be used as a wound cavityfiller.

Example 3

Chitosan Fibres Treated with Acid at Low Temperature and SubsequentlyHeat Treated.

Solutions containing 50 gram 96% ethanol, 2.5 gram water and 35 mmoleacid (mixtures of acetic and lactic acid) were prepared. To thesesolutions, 5 gram chitosan fibre sample was added and the samples weretreated in the solutions at room temperature for 24 hours. Then thefibres were rinsed in 96% ethanol and dried. When the samples were dry,they were heat treated for 6 hours at 100° C. in an oven. Finally, thesamples were sterilised by beta irradiation (1*30 kGy).

The absorption and cohesion of the samples were measured and the resultis shown in Table 3 (based on triple measurements).

TABLE 3 Sample Mole % acetic Absorption (g/g) Cohesion No. acid* 24hours (category) 1a 100 12 4 1b 80 15 2 1c 60 9 1 1d 20 0 0 1 0 0 0 *Oftotal acid content. The remaining acid content was lactic acid.

This example also shows, that the optimal quantity of the first acid isnot is the same for chitosan fibres treated with acid and a subsequentlyheat treatment, as for fibres treated with heat during the acidtreatment. When the chitosan fibres are treated with acids at lowtemperature, with a subsequent heat treatment of 100° C., the amount ofthe first acid should be kept below 40%.

Example 4

Chitosan Fibres Treated with Acid at Low Temperature and a SubsequentHeat Treatment.

A solution containing 100 gram 96% ethanol, 5 gram water, 2 gram aceticacid and 0.8 gram 90% lactic acid was prepared. To this solution, 5 gramchitosan fibre sample was added and the sample was treated in thesolution at room temperature for 1 hour. After the treatment the fibreswere rinsed in 96% ethanol and dried. When the sample was dry, it washeat treated at different temperatures and periods in an oven. At lastthe samples were sterilised using beta irradiation (1*30 kGy).

Table 4a is showing the absorption after 24 hours of the samples heattreated at different temperatures and periods.

TABLE 4a Temp. Time 80° C. 110° C. 140° C. 170° C. 0 minute 17 1 minute X* X X 15 2 minutes X X X 16 5 minutes X X X 11 15 minutes X X 18 11 ½hour X 15 11  9 1 hour 14 15  9 <10  2 hours 13 16 16 <10  4 hours 12 1512 X 8 hours 13 15 <10  X *When X is stated, the absorption was notmeasured

Table 4b shows the cohesion of samples heat treated at differenttemperatures and times.

TABLE 4b Temp. Time 80° C. 110° C. 140° C. 170° C. 0 minute 0–1 1 minute X* X X 2–3 2 minutes X X X 3 5 minutes X X X 4 15 minutes X X 3 4 ½hour X 3 3–4 4–5 1 hour 2 3 4 5 2 hours 3 3–4 4 5 4 hours 3 3–4 4–5 X 8hours 3 4 5 X *When X is stated, the cohesion was not measured

This example demonstrates, that when the fibres are acid treated at lowtemperature, a subsequent heat treatment is needed to make the modifiedchitosan fibres gelling and insoluble in water. If the fibres not areheat treated, they will dissolve when they contacted with water orexudate.

The more severe heat treatment the more water insoluble the chitosanfibres will become. There is also a tendency for less absorbent fibresusing a severe heat treatment.

Example 5

The Influence of the Quantity of Acid in the Heat Treatment.

In a reaction vessel 200 grams of 96% ethanol was mixed with 6 grams ofwater and different amounts of lactic acid (see table 5). To thissolution 20 grams of chitosan fibres were added and the suspension wastreated at the boiling point of the non-solvent for app. 4 hours underreflux. Then the fibres were washed twice in ethanol. The samples weresterilised by 1*30 kGy electron beam. Hereafter the absorption andcohesion of the fibres were measured.

Table 5 is showing the absorption and cohesion as a result of thequantity of acid in the combined acid and heat treatment (the resultsare a average of 3 measurements).

TABLE 5 Gram 90% Mmole lactic acid Sample lactic acid in the per gramAbsorption Cohesion No. solvent chitosan (g/g) (category) 5a 16 8 53 25b 10 5 16 3–4 5c 6 3 12 4

To obtain highly absorbent fibres, more than 5 mmole lactic acid pergram chitosan is needed. To obtain fibres with high cohesion, the amountof acid should be minimised to below 8 mmole lactic acid per gramchitosan.

Example 6

Use of Different Non-Solvents in the Acid Treatment.

A sample was treated as in example 5a, except that 1-propanol or1-butanol was used instead of 96% ethanol. Each non-solvent was preparedin such a manner, that there was 7 grams of water per 100 gram alcohol.The acid treatment was carried out at the boiling point of the nonsolvents for app. 4 hours. After the treatment the samples were washedand sterilised. The absorption and gellability were measured. Theresults can be seen in Table 6.

Table 6 is showing the absorption and cohesion as a results of the usednon-solvent in the combined acid and heat treatment (the results are aaverage of 3 measurements).

TABLE 6 Boiling point of Absorption Sample Used non-solvent after 24hours Cohesion No. non-solvent (° C.) (g/g) (category) 6a Ethanol 78 532 6b 1-Propanol 97 48 2–3 6c 1-Butanol 117 43 3

These results show, that the higher boiling point of the non-solvent,the lower cohesion of the modified chitosan fibres is obtained. Theresults demonstrates further, that when the fibres are treated innon-solvent with a high boiling point, the absorption is minimised, ifthe process time is constant.

Example 6a

Fibres treated with a limited amount of acid at an elevated temperature.

70 grams of 96% ethanol were mixed in a container with 6.5 and 8.0 gramsof lactic acid respectively. To this solution 10 grams of chitosanfibres were added. The container were sealed and placed in an autoclave(125° C. for 70 minutes). After the treatment the samples were washedand sterilised. The absorption and cohesion were measured. The resultscan be seen in Table 6a.

TABLE 6a Absorption after Sample Acid/chitosan 24 hours Cohesion No.(Mmole/g) (g/g) (category) 6aa 8 48 2 6ab 6.5 35 3

Table 6a shows that it is possible to convert chitosan fibres in arelatively short time by increasing the temperature and that the fibresbecomes more cohesive by decreasing the level of acid per gram chitosan.

Example 7

4 grams of sample 5a (non-sterile) was mixed by carding with differentquantities of calcium alginate fibres or carboxy methyl cellulosefibres. The fibre mixtures were sterilised (1*30 kGy). The absorptionand cohesion of the sterile samples were measured.

Table 7 demonstrates the absorption and cohesion for fibre samplescomprising mixtures of anionic and modified chitosan fibres (the resultsare averages of 3 measurements).

TABLE 7 Quantity of Absorption Sample Type of anionic anionic fibresafter 24 Cohesion No. fibres (grams) hours (g/g) (category) 7a CalciumAlginate 4 36 3 7b CM-Cellulose 4 35 3 7c CM-Cellulose 1 34 3

This example shows, that if the chitosan fibres are mixed with alginateor carboxy methyl cellulose fibres, the cohesion of the fibresincreases, while the absorption decreases.

Example 8

Chitosan Fibres Treated with Acid at Low Temperature and a SubsequentHeat Treatment.

A solution containing 100 gram 96% ethanol, 5 gram water, 6.4 gram 90%lactic acid and 1.0 gram acetic acid was prepared. To this solution, 10grams of chitosan fibres were added and the sample were treated in thenon-solvent at room temperature for 1 hour. After the treatment thefibres were rinsed in 96% ethanol and dried at 30° C. When the sampleswere dry, the sample was treated with heat. The heat treatment wascarried out at different temperatures and periods in an oven. After theheat treatment the samples were sterilised using beta irradiation (1*30kGy).

Table 8a demonstrates the absorption and cohesion (absorption(g/g)/cohesion) of the samples heat treated at different temperaturesand periods (measured as a triple measurement on sterile samples).

TABLE 8 Temp. Time 110° C. 135° C. 160° C. 0 minute soluble 2 minutes xx soluble 8 minutes x soluble 44/2 20 minutes x soluble  40/2–3 1 hour10/1 27/2  17/4 4 hours 10/1 23/3–4 x

The results demonstrate, that the higher temperature the subsequent heattreatment is processed at, the higher absorption is obtainable. Also theduration of the heat treatment is influenced by the heat treatment (thehigher temperature, the shorter time is needed to obtain insolublefibres).

Example 9

Chitosan Fibres Treated with Different Quantities of Acid at LowTemperature and a Subsequent Heat Treatment.

The samples were processed as in Example 8, but with followingadjustment: In Example 9a the only used acid was lactic acid (8 gram 90%lactic acid per 10 gram chitosan), and in Example 9b the acid volumeswere 4.8 grams 90% acetic acid and 2 grams acetic acid.

After acid treatment both samples were heat treated at 1.60° C. for 10minutes. Hereafter the absorption and cohesion was measured.

The absorption and cohesion result are listed in Table 9.

TABLE 9 Absorption after 24 hours Cohesion Sample No. (g/g) (category)9a 43 2 9b 27 3

This example is showing, that when the chitosan fibres are modified in atwo step process (acid treatment at room temperature and subsequently aheat treatment), only one acid is needed to obtain fibres with cohesionenough to removal in one piece is possible. The example alsodemonstrates, that the more acetic acid in the treatment, the highercohesion is obtained, but the absorption decreases with increasingamounts of acetic acid.

Example 10

Preparation of a Woven Fabric Comprising Chitosan Fibres.

The modified chitosan fibres (sample 9a in Example 9) were processedinto yarn, and a woven fabric was made. The material was cut in squaresof 10*10 cm², packed and sterilised.

The woven fabric is suitable as a wound care device, to cover and gelupon a wound site while absorbing a high amounts of wound exudate.

Example 11

Preparation of a Woven Fabric Comprising Chitosan Fibres and Cotton.

The modified chitosan fibres (sample 9a in Example 9) were processedinto yarn and weaved with cotton to produce a woven fabric (40% chitosanand 60% cotton). The material was cut in squares of 10*10 cm², packedand sterilised.

The woven fabric is suitable as a non adherent wound dressing to placedirectly on a wound and protect the wound against the secondary wounddressing and from drying out.

Example 12

Comparing Treated Fibres and Powder.

10 grams of chitosan powder was treated as the fibres in sample 1c (butnot sterilised). FIG. 1, a colour photo, shows the difference incohesion between powders and the fibres prepared according to thisinvention (the fibres and powder are treated exactly the same way andboth samples are non-sterile). The figure shows both the fibres fromsample 1c (non-sterile) and the powder prepared as sample 1c.

The powder is discrete insoluble absorbent particles, while the fibresturns into a cohesive mass. Thus, this example demonstrate that thecohesion may only be obtained by the use of fibres, while the sameeffect will not be achieved by using powderous chitosan. The powderparticles are not suitable as the main ingredient in a wound careproduct if removal in one piece is desired, while the fibres indeed areuseful as the main ingredient in a wound care device.

Example 13

The Maximum Absorbency of Some Selected Fibres from the EarlierExamples.

The maximum absorbency is measured after 3 days in solution A after thesame method as absorption after 24 hours. The absorption is measured onnon-sterile samples.

TABLE 13 Absorption after Maximum absorption Cohesion Sample no. 24hours (g/g) (g/g) (category) 5a 53 70 2 6b 48 47 3

This example is showing that the absorption is increasing in up to 3days when the cohesion is evaluated to 2. If the cohesion is evaluatedto 3, the maximum absorption is reached within the first 24 hours.Samples with lower cohesion may have higher absorption. This is due tothe samples swellability, which is higher, when the sample is lesscohesive.

Example 13b

A non-sterile sample of sample 5a and of 6b was cut to app. 50 mmlengths and a wound dressing was formed by first carding the cut fibresto form an approximate 20 g/m² web, then cross folding the this webneedling to give a resultant non-woven fabric of approximately 100 g/m²,then a 10 cm×10 cm square was cut to form the fabric. The square of thefabric was packaged and sterilised using an electron beam dose of 30kGy.

The sterile non-woven wound care device of sample 5a had an absorbencyof 60 g/g and 0.59 g/cm².

The sterile non-woven wound care device of sample 6b had an absorbencyof 46 g/g and 0.48 g/cm². The wound care device is easily removed in onepiece from a exuding wound.

Example 14

Prolonged Acid Treatment.

A sample was treated as sample 1a, but the acid treatment was prolongedto 10 hours instead of 4 hours.

The absorption and cohesion is listed in table 14 (as a average oftriple measurements).

TABLE 14 Absorption after Absorption after 3 Cohesion Sample no. 24hours (g/g) days (g/g) (category) 14 55 74 2

This example demonstrates, that only one acid is needed in the acidtreatment when the is conducted at the boiling point of ethanol (below85° C.). It is possible to prepare modified chitosan fibre samples withextremely high absorption compared to prior art.

Example 15

This example demonstrates the method of making suberabsorbent gellable,substantially water insoluble modified chitosan fibres by partly carboxymethylating the chitosan fibres. A solution containing 100 gram water,15 gram sodium hydroxide, 45 gram sodium chloro acetate and 100 gram ofethanol was prepared. 10 grams of chitosan fibres were added to thesolution and the solution was heated to the boiling point of thesolution and treated until the fibres was partly carboxy methylated.After the treatment, the modified chitosan fibres was washed in analcohol bath containing an acid. The fibres were finally dried.

The fibres were processed into an sterile non-woven fabric (as inExample 1b).

1. A wound care device comprising chitosan fibers modified by treatmentwith an acid in a solvent wherein said chitosan fibers are insoluble insaid solvent, capable of absorbing liquid to form a swollen, coherentgel having an absorption higher than about 20 g/g, wherein said fibersare manufactured into a fiber rope, knitted, woven or non-woven sheet orpouch or in the form of an island dressing.
 2. A wound care deviceaccording to claim 1, characterized in that the chitosan has a viscosityof less than 1000 cP measured on a 1% w/w chitosan solution in 1%aqueous solution of acetic acid.
 3. A wound care device according toclaim 1 characterized in that the proportion between the length anddiameter of the fibers is at least
 25. 4. A wound care device accordingto claim 1, characterized in that the chitosan fibers have an absorptionhigher than about 25 g/g.
 5. A wound care device according to claim 1,characterized in that the ratio of acid to chitosan is from about 5 to 7mmol acid per gram chitosan.
 6. A wound care device according to claim1, characterized in that the ratio of acid to chitosan is from about3–7.5 mmol acid per gram chitosan.
 7. A wound care device according toclaim 1, characterized in that the ratio of acid to chitosan is from 4to 10 mmol acid per gram chitosan.
 8. A wound care device according toclaim 1, characterized in that the ratio of acid to chitosan is from 3to 15 mmol acid per gram chitosan.
 9. A wound care device according toclaim 1, characterized in that the chitosan fibers have an absorptionhigher than about 30 g/g.
 10. A wound care device according to claim 1,characterized in that the proportion between the length and diameter ofthe fibers is more than
 200. 11. A wound care device according to claim1, characterized in that the proportion between the length and diameterof the fibers is more than
 80. 12. A wound care device according toclaim 1, characterized in that the chitosan has a viscosity from about40 cP to about 200 cP, measured on a 1% w/w chitosan solution in 1%aqueous solution of acetic acid.
 13. A wound care device according toclaim 1, characterized in that the chitosan has a viscosity of less than500 cP, measured on a 1% w/w chitosan solution in 1% aqueous solution ofacetic acid.
 14. A wound care device according to claim 1, characterizedin that the chitosan has a viscosity of less than 300 cP, measured on a1% w/w chitosan solution in 1% aqueous solution of acetic acid.